Water-soluble heterocyclic therapeutic compounds



' Patented UNITED STATES PATENT OFFICE WATER-SOLUBLE HETEROCYCLIC THERA- PEUTIC COMPOUNDS Jonas Kamlet, Brooklyn, N. Y., asslgnor to Merck & (30., Inc., Rahway, N. J.', a corporation of New Jersey No Drawing.

4 Claims.

@NHSOrONlLCHLSOLONa This compound may be prepared by the reaction of 2-sulfanilylamidopyridine and sodium formaldehyde-bisulfite (or formaldehyde and sodium bisulflte) in an aqueous medium at advanced temperatures. It may also be obtained either by converting 2-sulfanilylamidopyridine to its soluble sodium salt and reflexing a solution'oi the latter with sodium formaldehyde-bisulflte, or by reacting equimolecular proportions of 2- sulfanilylamidopyridine, sodium sulfite and formaldehyde, for the production of 2 (p-(N- sodium methylene-sulfonate) aminobenzenesulphon- (N-sodium) amino) -pyridine, which is then reacted with one mole equivalent of dilute mineral or organic acid to yield the monosodium salt.

The medium for this reaction is not necessarily limited to aqueous solutions. It may be effected in a medium consisting of one or more members of a group comprising the well-known hydroxyalkyi solvents, i. e., the aliphatic alcohols, the aliphatic glycols and glycerin, as well as aqueous solutions of these solvents. Thus, equimolecular proportions of 2-sulfanilylamidopyridine and sodium formaldehyde-bisulfite (or formaldehyde and sodium bisulflte) in 50 per cent aqueous ethanol are refluxed on the boiling water-bath for two hours. The solvent is then evaporated oil until a small volume of solution remains. This residue is now added in the cold to 50 volumes of acetone, and the copious, precipitated, white compound is filtered off. The 2- (p-(N-sodium methylene-sulfonate) aminobensenesuiphonamido)-pyridine thus obtained is a Application December 29, 1939, Serial No. 311,521

1 fections.

fine, white, microcrystalline powder, readily soluble in water. It is stable at all temperatures up to its melting point.

2-(p-(N-sodium methylene-sulfonate) aminobenzenesulphonamido) pyridine, precipitated from acetone, forms white microcrystalline particles melting at 208-210 0.; with decomposition. It is soluble in water at 37 C. to the extent of about 20 per cent, moderately soluble in alcohol, completely insoluble in acetone, ether, benzene, chloroform and ligroin. This compound is a weak reducing agent and may be determined quantitatively by titration with acidified permanganate, which it decolorizes. With alkaliearth metal salts'and with heavy-metal salts, it forms insoluble or slightly soluble crystalline compounds.

The tolerance of experimental animals to 2(p- (N-sodium methylene-sulfonate) aminobenzenesulphonamido) -pyridine is good. Mice will tolerate daily injections of 1.5 grams per kilo of body weight over a prolonged period. When mice are infected with 100 lethal doses of a virulent culture of pneumococci, 50 per cent recovery is obtained in these mice by the daily administration of 0.5 gram per kilo 01' body weight, in four equal injections. Orally, the maximum tolerance of this compound in mice is about 4.0 grams per It has good chemotherapeutic specificity against pneumococcic, streptococcic and gonococcic in- For therapeutic use, 2-(p-(N-sodium methylene sulfonate) aminob'enzenesulphonamido)- pyridine can be compressed into tablets for oral administration, in which the drug's marked solubility and rapid absorption by the blood stream are advantageous. It may be distributed as a powder in weighed amounts into evacuated ampuls to be dissolved in sterile water immediately prior to injection. A solution of the drug may be directly prepared, packaged and sterilized, for parenteral use, as Example 2 describes.

The compound 2-(p-(N-sodium methylenesulfonate) aminobenzenesulphonamido) pyridine is miscible and compatible with serum in all proportions and may be administered parenterally in admixture with type-specific antipneumococcic serum. In such a use, it is important that the type or the causative pneu- H M-m.

This compound is Z-(p-(N-sodium methylene-sulfonate) aminobenzenesulphon (N sodium) amido) -pyridine. It is precipitated from acetone as a white, amorphous compound, melting at 236-2l0 C., with decomposition. rear-lily soluble in water, moderately soluble in alcohol, insoluble in acetone, ether and other organic solvents.

Chemically and pharmecologically, it closely resembles the monosodium salt described in the foregoing.

Although this disodium salt is too alkaline for parenteral administration, it may be given by mouth or, in solution, by rectum. A solution of the disodium salt, suitably adjusted to pH 7.5, may be admixed with type-specific anti-pneurnococcic serum, for parenteral administration.

The pH of a freshly prepared 10 per cent solution of Z-(p-(N-sodium methylene-sulionate) aminobenzenesulphonamido)-pyridine is about 5.6. The pH of a freshly prepared 10 per cent solution of 2-(p- (N-sodium methylene-Sultanate) aminobenzene-sulphomN'-sodium) amido)-pyridine is about 11.0. Each of these compounds may be adjusted to pH 7.5 (the pH of the blood) and will remain stable when so adusted.

ion the dlsodiuin salt is reacted with an equivalent quantity of Bil per cent acetic acid or the free acid is formed:

I NHSOr- NH-CHLSOIOH s G This compound is 2-(p-(N-methylene-sulfonic acid) aminobenzene sulphonamido)-pyridine, obtained from its aqueous solution as white, amorphous particles melting at 2l6-220 C., with decomposition. When heated with strong mineral acids, this compound yields sulfapyridine, formaldehyde and sulphur dioxide. This acid is soluble in caustic alkali solutions, moderately soluble in water and alcohol, and insoluble in all other organic solvents. It is useful as the parent substance of the foregoing monos'odium and disodium derivatives and of alkaline earth, heavy metal, and organic salts.

The following examples are given by way of illustration and not of limitation, as it is obvious that certain modifications may be made in the steps of these processes, and in the kinds and proportions of the materials employed, without departing from the spirit and scope of the invention and the purview of the claims.

Example 1 To a solution or 75 grams of 40 percent formaldehyde solution and 105.0 grams of chemically pure sodium bisulfite in 2 liters of water is added soon grams of fz-sulizanilylamidopyridine pow der. The mixture is heated on the boiling waterdill HOfiHaSGzONaHrO) A funnel is placed in the neck or the an contents are heated to boiling. Sputtering:

posited on the walls of Washed back into sch. steam. I

After boiling gently for 15 to inimi' clear solution is obtained. is emoved and boiling is continued for mint, longer. The volume of the hot solution will now be about 1800 to 1850 cc. and its pH The pH is adjusted to 7.5 by clro tion of a. 5 per cent sodium. hydro e so ut' with the aid of a potentiometer, and the of the solution is brought to litres t tilled water. The fiaslr is stopperecl with cool spontaneously by standing at room temperature for an hour.

The slight amount of unreacted 2-sulfanilylamidopyridine that forms on standing is on the clear, almost color" triouted into sterile are now sterilized hot, and so e cent solution oi innate) enesu ready for clinical use.

Examplcfi 52 grams of anhydrous sodium sulflte is dis solved in 800 cc. of water. To the resultant solution are then added 32.5 grams of per cent formaldehyde solution, 73.5 grams of 36 percent acetic acid and grams of Q-SuIfaniIylamidopyridine powder. The mixture is refluxed until a clear solution is obtained, 1 gram of activated animal charcoal is now added, the refluxing is then continued for thirty minutes, and the hot solution is filtered. The clear, almost colorless filtrate, when cooled .to room temperature, has a pH oi about The solution is now evapo rated to dryness in vacuo. The residue is H extracted with tour successive zoo cc. pot of cold absolute alcohol until tree oi soul 11 tate, recrystallized m aqueous solution .1: cipitation with volumes oi ccetoi tered off, and dried to constant weight.

The white product thus obtained is fro uhle in water and, on analysis, is found 2- (p- (N-sodium methylene-sulfonate) amino senesulphonamldo)-pyridine. The yield to grains.

ieum occic methylene-sulfonate) aminobenzenesulphonamido)-pyridine, which has been adjusted to a pH of 7.5 with 5 percent NaOH, or with 10 cc. of a sterile solution containing 1 gram of Z-(p-(N-sodium methylene-sulfonate) amino-benzene-sulphon (N'-sodium) amidM-pyrldine, which has been adjusted to a pH of 7.5 with 5 percent Ho]. The resulting mixture is slowly injected intravenously, and is well tolerated.

Example 5 One gram of sterile z-(p-(N-sodium methylene-sultonate) aminobenzenesulphonamido)-pyridine powder is dissolved in 10,000 units of Felton antipneumococcic rabbit serum. The powder dissolves freely in the serum. Precautions are taken to preserve sterility. The resultant solution is slowly injected intramuscularly or intravenously after it has been determined that the patient is not allergically sensitive thereto.

I claim: 1. Compounds having the formula:

in which X and Y are taken from the class consisting of hydrogen and sodium, and in which Y is sodium when X is sodium.

2. 2-(p(N-sodium methylene-Sultanate) amlnobenzenesulphonamido) -pyridine.

3. 24p-(N-sodium methylene-Sultanate) aminobenzenesulphon (N'-sodium) dine.

4. 2-(p-(N-methylene-sulfonic acid) aminobenzenesulphonamido) -pyridine.

JONAS KAMLET.

amido) -pyri- 

